A multicentre, open-label phase II study of Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO) as first-line treatment in patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Purpose Chemotherapy remains the primary treatment for metastatic gastric/GEJ cancer but optimal agents and schedule remain controversial. This study examined the safety and efficacy of first-line Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO). Patients and Methods Eligible patients with HER2-unamplified/unknown, metastatic gastric/GEJ adenocarcinoma were treated with 21-day cycle IXO at dose level 1 (DL1: Day 1 O-100 mg/m2 & I-160 mg/m2 IV, Day 2-15 X-1900 mg/m2/day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m2 & I-120 mg/m2 IV, Day 2-15 X-1425 mg/m2/day PO divided doses). This Bryant and Day two-stage designed study had dual primary endpoints of objective response rate (ORR) and toxicity. Secondary endpoints were overall survival (OS) and progression-free survival (PFS). Results Fifty patients were enrolled and received a median of 7 cycles. After accrual of 9 patients at DL1, evaluable RR was 88% however dose limiting toxicity (DLT) rate was 56% thus doses were adjusted to mIXO. Fifteen patients accrued at mIXO had a RR of 60% and DLT rate of 13% allowing continuation to stage 2. Overall, 48 and 49 patients were evaluable for efficacy and safety, respectively, with ORR of 54% and DLTs in 24% of patients (DL1 = 56%; mIXO = 18%). Disease control rate was 85%. The most frequent grade 3/4 adverse events were diarrhea, neutropenia, fatigue, hypokalemia, and nausea. Median PFS and OS were 7.5 and 13.0 months, respectively, with a median follow-up of 9.7 months. Conclusion mIXO demonstrates promising ORR, PFS, OS, and acceptable toxicity compared to standard triplet regimens. IXO should be evaluated in phase III trials.

Variable Endoscopist performance in proximal and distal adenoma detection during colonoscopy: a retrospective cohort study.

BACKGROUND: Adenoma Detection Rate (ADR) is a validated colonoscopy quality indicator. In addition to overall ADR, Distal and Proximal Adenoma Detection Rates may provide important colonoscopy quality information. The goal of this study is to determine the association between distal and proximal adenoma detection (AD) and to identify factors contributing to overall, distal, and proximal AD. METHODS: This is a retrospective cohort study of patients with a noted family history of CRC or positive fecal occult blood test who underwent a screening colonoscopy at a regional colorectal cancer (CRC) screening center between May 2009 and December 2011. Data regarding patient demographics, procedure details, endoscopist characteristics and polyp histology were captured. The main outcomes measured were overall, distal, and proximal AD. RESULTS: 1907 patients were included. The median age was 60 years and 42% were male. Endoscopist median overall ADR was 25% (30% male, 21% female). Endoscopist distal ADR was only modestly associated with their proximal ADR (Spearman Rank: 0.51 p = 0.11). Highest overall ADR (29 to 45%) was found for endoscopists whose distal and proximal ADRs were above the group median. In multivariate analysis, factors associated with overall, distal, and proximal AD included age, sex, and endoscopist practicing experience. CONCLUSION: Inclusion of distal and proximal ADRs, in addition to overall ADR, in colonoscopy quality assessment provides the more accurate feedback on endoscopist performance.

Improvisations in classic and modified techniques of flap surgery to improve the success rate for pressure ulcer healing in patients with spinal cord injury.

The recurrence of pressure ulcers (PrUs) and dehiscence of reconstructive flap have always been a problem. The present study aimed to evaluate the results of reconstructive flap surgeries in patients with spinal cord injury (SCI) having PrUs, using classic and modified flaps with improvisations to decrease wound dehiscence, flap necrosis and tension in flap. This is a prospective clinical study. The setting was a tertiary care centre in northern India. Thirty-five patients with SCI having 37 stage III and IV PrUs. PrUs were treated using classic and modified flaps with improvisations. The outcome was evaluated using criteria of wound dehiscence, flap necrosis and recurrence. The results of flap surgery were excellent in 32 (86·48%) patients, good in 4 (10·81%) patients and poor in 1 (2·7%) patient. Partial flap necrosis (2·7%), low incidence of PrU recurrence rate at flap site (5·4%) and overall PrU recurrence (11·4%) were the complications observed. Improvisation of classic and modified techniques of flap surgeries along with reinforcement of general care principles of paraplegia can be effective in minimising complications often associated with PrU reconstructive surgery thus improving the ultimate outcome.

A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer.

AIM: This phase I/II study of saracatinib in combination with gemcitabine in patients with advanced pancreatic cancer was conducted by the NCIC Clinical Trials Group. The aims were to define the recommended phase II dose (RP2D) of saracatinib when combined with gemcitabine, and assess the efficacy of this combination in advanced pancreatic cancer. PATIENTS AND METHODS: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and no prior chemotherapy. In phase I saracatinib was escalated in combination with gemcitabine (1000 mg/m(2)) to determine the recommended phase II dose (RP2D). The study was then expanded to a single arm phase II trial using a Simon 2-stage design. The primary endpoint was objective tumor response (OR) plus stable disease ≥ 4 months (SD4) rate; if ≥ 8 patients had OR+SD4, the study would proceed to stage 2. RESULTS: Thirteen patients were enrolled into the phase I portion of this study. Saracatinib 175 mg PO daily was chosen as the RP2D in combination with gemcitabine. Twenty-one additional patients were then enrolled at the RP2D (phase II). Of the 22 response evaluable patients treated at the RP2D, 9 patients (40.9%) had progressive disease, 6 patients (27.3%) had stable disease for less than 4 months, 5 patients (22.7%) had SD4, and 2 patients (9.1%) had a partial response to treatment. Objective criteria for continuing to stage 2 were thus not met and the trial was closed following the accrual of 34 patients. CONCLUSION: Saracatinib 175 mg daily in combination with gemcitabine is well tolerated but the combination did not improve efficacy over what would be expected from gemcitabine alone.

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2019.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2019 was held in Morell, Prince Edward Island, 19-21 September 2019. Experts in medical oncology, radiation oncology, and surgical oncology who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of anal, colorectal, biliary tract, and gastric cancers, including: radiotherapy and systemic therapy for localized and advanced anal cancer; watch and wait strategy for the management of rectal cancer; role of testing for dihydropyrimidine dehydrogenase (DPD) deficiency prior to commencement of fluoropyrimidine therapy; radiotherapy and systemic therapy in the adjuvant and unresectable settings for biliary tract cancer; and radiotherapy and systemic therapy in the perioperative setting for early-stage gastric cancer.

Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial.

IMPORTANCE: Previous communication has reported significant improvement in overall survival (OS) when using doxorubicin plus sorafenib in the treatment of advanced hepatocellular cancer (HCC). OBJECTIVE: To determine if doxorubicin added to sorafenib therapy improves OS, with stratification for locally advanced and metastatic disease. DESIGN, SETTING, AND PARTICIPANTS: This unblinded randomized phase 3 clinical trial was led by Alliance in collaboration with Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Canadian Cancer Trials Group, and Southwest Oncology Group. It was launched in February 2010 and completed in May 2015; data were also analyzed during this time frame. Patients with histologically proven advanced HCC, no prior systemic therapy, Child-Pugh grade A score, Eastern Cooperative Oncology Group performance status of 0 to 2 (later amended to 0-1), and adequate hematologic, hepatic, renal, and cardiac function were eligible. The OS primary end point had a final analysis planned with 364 events observed among 480 total patients with 90% power to detect a 37% increase in median OS. INTERVENTIONS OR EXPOSURES: Patients received either 60 mg/m2 of doxorubicin every 21 days plus 400 mg of sorafenib orally twice daily or the sorafenib alone, adjusted to half doses for patients with bilirubin levels of 1.3 to 3.0 mg/dL. MAIN OUTCOMES AND MEASURES: The primary end point was OS, and progression-free survival (PFS) was a secondary end point. RESULTS: Of 356 patients included in the study, the mean (SD) age was 62 (10.1) years, and 306 (86.0%) were men. Although it was planned to include 480 patients, the study was halted after accrual of 356 patients (180 patients treated with doxorubicin plus sorafenib and 176 with sorafenib alone) with a futility boundary crossed at a planned interim analysis. Median OS was 9.3 months (95% CI, 7.3-10.8 months) in the doxorubicin plus sorafenib arm and 9.4 months (95% CI, 7.3-12.9 months) in the sorafenib alone arm (hazard ratio, 1.05; 95% CI, 0.83-1.31). The median PFS was 4.0 months (95% CI, 3.4-4.9 months) in the doxorubicin plus sorafenib arm and 3.7 months (95% CI, 2.9-4.5 months) in the sorafenib alone arm (hazard ratio, 0.93; 95% CI, 0.75-1.16). Grade 3 or 4 neutropenia and thrombocytopenia adverse events occurred in 61 (36.8%) and 29 (17.5%) patients, respectively, being treated with doxorubicin plus sorafenib vs 1 (0.6%) and 4 (2.4%) patients treated with sorafenib. CONCLUSIONS AND RELEVANCE: This multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of OS or PFS in patients with HCC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01015833.

Phenytoin Toxicity During Neoadjuvant Concurrent Capecitabine and Radiation Therapy for Rectal Adenocarcinoma: Case Report of a Drug Interaction.

Phenytoin toxicity occurs when serum levels exceed the therapeutic level, leading to symptoms such as nystagmus, slurred speech, and decreased coordination. This toxicity is sometimes caused by drug interactions. Interactions between phenytoin and capecitabine are not commonly documented. We report the case of a 52-year-old man taking phenytoin for atypical meningioma who developed symptoms of phenytoin toxicity while receiving capecitabine in the treatment of rectal adenocarcinoma.

A Phase I Study of Irinotecan, Capecitabine (Xeloda), and Oxaliplatin in Patients With Advanced Colorectal Cancer.

BACKGROUND: The objective of the present phase I study was to define the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of irinotecan, capecitabine, and oxaliplatin given in combination (IXO regimen) to patients with previously untreated, unresectable advanced or metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients received oxaliplatin followed by irinotecan as intravenous infusions on day 1, with oral capecitabine taken twice daily (BID) on days 2 to 15 of a 3-week cycle. The dose ranges were explored as follows: oxaliplatin, 75 to 120 mg/m2; irinotecan, 160 to 230 mg/m2; capecitabine, 750 to 1000 mg/m2 BID. Dose escalation was performed individually for each drug at each dose level according to the type and severity of toxicity encountered in the previous cohort. RESULTS: A total of 39 patients were enrolled at 7 dose levels and the MTD. The recommended doses for phase II evaluation were oxaliplatin 100 mg/m2, irinotecan 160 mg/m2, and capecitabine 950 mg/m2 BID. Diarrhea and febrile neutropenia were DLTs. Of the 39 enrolled patients, 26 (67%) had confirmed objective responses. The median progression-free survival was 11 months, and the median overall survival was 25 months. The survival rate at 5 years was 23%. CONCLUSION: The IXO regimen has a manageable toxicity profile with promising antitumor activity as first-line treatment of advanced and metastatic CRC.

Phase 1 and pharmacokinetic study of intravenous irinotecan in refractory solid tumor patients with hepatic dysfunction.

PURPOSE: To determine the recommended starting doses and pharmacokinetics of irinotecan in cancer patients with impaired liver function treated on a weekly schedule. EXPERIMENTAL DESIGN: Patients with solid tumors who had impaired liver function were enrolled into four groups based on baseline serum total bilirubin and aspartate aminotransferase (AST)/alanine aminotransferase (ALT): Group 1 (n = 19): total bilirubin 1.5 to 3.0 x institutional upper limit of normal (IULN) and ALT/AST

Increased prevalence of colonic adenomas in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is the most common lethal genetic illness in the Caucasian population. Studies have shown that CF patients are at an elevated risk of developing colon cancer. Colonic adenomas are the precursors of colon cancer. This study aims to determine the prevalence of adenomas in patients with cystic fibrosis. METHODS: All patients were recruited prospectively at The Ottawa Hospital Cystic Fibrosis Clinic from 2010 through 2015. Baseline demographic and cystic fibrosis disease characteristics were collected from the clinic's CF patient database. Upon presentation at the endoscopy unit, and after a brief history and physical exam, a colonoscopy was performed. Polyps were resected if detected and sent to the pathology department for characterization. Findings were compared with a control group (pairing each CF patient with 5 age and sex-matched controls) of near-average risk patients who underwent a colonoscopy at the same center. RESULTS: Of the 33 patients that provided informed consent to participate in the study, 30 patients underwent colonoscopy and 13/30 (43.3%) were found to have colonic adenomas compared to 7 (4.7%) of the 150 control patients. The relative risk ratio for adenoma detection in a CF patient as compared to a matched control patient was 9.29 (95% CI 4.04-21.31), p<0.01. CONCLUSIONS: Colonic adenomas are more prevalent in CF patients compared to the general population. This study suggests the need for additional research to support recently published screening guidelines for CF patients.

An HPLC method for the measurement of 5-fluorouracil in human plasma with a low detection limit and a high extraction yield.

High performance liquid chromatographic (HPLC) techniques for the quantification of 5-fluorouracil (5-FU) in human plasma have been reported in the literature, however, a low limit of detection was generally found to result in a comparatively low extraction yield. We have developed a simple, rapid and sensitive HPLC method for the measurement of 5-FU in plasma which provides both a low limit of quantification and a high extraction yield. This method involves the solid phase extraction of 5-FU from a 500 microl plasma sample. The extract is then injected into an HPLC system equipped with a C18 (mu)Bondapak column, and a UV detector set at 260 nm. Ethyl acetate and potassium dihydrogen phosphate are used for the solid phase extraction and the HPLC mobile phase, respectively. This method provides in a good baseline, a sharp and symmetrical peak for 5-FU, and a high resolution between 5-FU and the internal standard. The retention time of 5-FU using this method is 4.7 min with a limit of detection of 5 ng/ml, and an extraction yield of 96.2+/-0.5% (SE). The next injection is possible in 11 min, and the coefficients of variation are 4.2-8.9% for interday precision, and 5.2-10.6% for day-to-day reproducibility. An HPLC method has been developed that has a low limit of detection and a high extraction yield. This technique was successfully applied in a clinical pharmacokinetic study of 5-FU.

Subungual exostosis of the great toe: a case report and tumor overview.

UNLABELLED: Subungual exostosis is an acquired, benign, and solitary bone tumor of the distal phalanx occurring beneath or adjacent to nail. A 18-year-old man presented with a lump, ulceration, and pain on his right big toe. This complaint was present for the past 2 years. Initially, lump and pain were present, and since the past 6 months ulceration and superadded infection occurred. Plain radiograph showed a calcified lesion that was continuous with the phalangeal cortical surface in the distal dorsal aspect of the big toe. Excisional biopsy with complete nail removal and reconstruction of the tip of the toe were done. Histopathology confirmed the diagnosis of subungual exostosis. Clinical or radiological recurrence was not observed after 26 months of follow-up. The case is reported to present the tumor overview and to highlight that the diagnosis of this benign lesion should not be missed. Clinical and radiological features allow early diagnosis and treatment thus preventing the lesion to progress to the stage of onycholysis. LEVEL OF EVIDENCE: Therapeutic, Level IV.

A phase II study of biweekly pemetrexed and gemcitabine in patients with metastatic breast cancer.

PURPOSE: Pemetrexed (PEM) is a novel folate antimetabolite which inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferase. This phase II study was designed to assess the efficacy of Gemcitabine (GEM) and PEM given in a novel schedule in metastatic breast cancer (MBC) patients. METHODS: Eligible patients had MBC and received one prior chemotherapy regimen for metastatic disease; Performance status (PS) 0-2; measurable disease (RECIST criteria). PEM(500 mg/m2) was administered intravenously (IV) over 10 min prior to GEM(1,500 mg/m2) IV given over 30 min on day 1 every 14 days. RESULTS: Median age of the 16 patients in the study was 54 years (range 33-77). Fourteen patients had a PS of 0/1 and were evaluable for response. There were no reported complete or partial responses, seven patients with stable disease, six patients with disease progression and one patient with unknown response. Most common toxicities were skin rash: Grade 1/2(8) and Grade 3/4(1). Grade 3/4 non-hematological toxicities were fatigue(1); anorexia(1); pneumonia(1); peripheral ischemia(1) and elevation of liver transaminases(1). Three patients experienced febrile neutropenia (FN). This study did not meet the predefined criteria to proceed with additional accrual. CONCLUSIONS: This regimen of PEM and GEM showed no clinical activity in the dose and schedule tested.

Phase II multicenter trial of anthracycline rechallenge with pegylated liposomal doxorubicin plus cyclophosphamide for first-line therapy of metastatic breast cancer previously treated with adjuvant anthracyclines.

PURPOSE: Anthracyclines are a component of breast cancer chemotherapy regimens in both adjuvant and metastatic settings. Anthracycline rechallenge for metastatic disease, for those previously exposed to adjuvant anthracyclines, may not be considered because of concerns about efficacy, tolerability, and cumulative cardiotoxicity. PATIENTS AND METHODS: This prospective, multicenter, single-arm, phase II trial examined the efficacy and safety of pegylated liposomal doxorubicin (PLD) 35 mg/m(2) plus cyclophosphamide 600 mg/m(2) as first-line therapy, delivered every 3 weeks, in 70 patients who developed metastatic disease more than 12 months after completion of an adjuvant anthracycline-containing regimen. Seven patients discontinued treatment early and were excluded from the efficacy analysis. RESULTS: After a median of six cycles, the objective response rate was 38%. An additional 33% of patients achieved stable disease lasting more than 6 months, for an overall clinical benefit rate of 71%. The estimated median time to progression was 12.2 months. Median overall survival time was 16.5 months. Clinical response was equally robust in patients with and without prior taxane exposure. Treatment was well tolerated. The most common grade 3 to 4 toxicities were palmar-plantar erythrodysesthesia (PPE; 10%), dyspnea (9%), and neutropenia (9%). One (1.4%) of 70 patients discontinued treatment as a result of PPE. One patient (1.4%) experienced an infusion reaction requiring discontinuation. No symptomatic cardiac events were observed. CONCLUSION: PLD plus cyclophosphamide is effective and well tolerated in patients with metastatic breast cancer who have received prior adjuvant anthracycline-containing chemotherapy. The majority of patients experienced a clinical benefit without any significant impact on cardiac function.

Phase I study of Tomudex and Doxorubicin in patients with locally advanced, inoperable or metastatic cancer (IND.98).

BACKGROUND: The primary objective of this Phase I study was to determine the maximum tolerated dose (MTD) and recommended phase II dose for Tomudex and Doxorubicin when given in combination to patients with advanced metastatic cancer. The secondary objective was to assess the toxicity profile. PATIENTS AND METHODS: Starting doses were Tomudex 2.5 mg/m2 i.v. bolus day 1 and Doxorubicin 30 mg/m2 i.v. bolus day 1, repeated every 3 weeks. Doxorubicin was escalated in increments of 10 mg/m2 to 60 mg/m2, followed by escalation of Tomudex in increments of 0.5 mg/m2 to 3.5 mg/m2, on six dose levels. Twenty-five patients received 127 cycles of therapy, with at least 3 patients treated at each dose level. RESULTS: There was no dose limiting toxicity (DLT) observed in the first five dose levels. Three of six patients on dose level six had DLT. Further dose escalation was not warranted and this was declared the MTD. Grade 3 or 4 granulocytopenia was observed in 16/25 patients, with associated fever in 3/25 patients. Responses were seen in this study with one complete response (duration 12.8 months) and 3 partial responses (median duration 8 months) in 21 evaluable patients. Fourteen patients had stable disease (median duration 2.5 months). All 4 responding patients and 10 patients with stable disease had gastric cancer. CONCLUSIONS: The recommended phase-II dose for this combination in future studies is Tomudex 3 mg/m2 and Doxorubicin 60 mg/m2 given every 3 weeks.

A phase II trial of ZD1839 (Iressa) 750 mg per day, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, in patients with metastatic colorectal cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) appears relevant in the pathogenesis and progression of colorectal cancer. After completing a phase I pharmacodynamic trial of ZD1839, we undertook a dose expansion trial to examine the antitumour efficacy and adverse effect profile of this agent in a homogeneous group of patients with metastatic colorectal cancer (CRC). EXPERIMENTAL DESIGN: Eligible patients with metastatic or recurrent CRC received ZD1839 750 mg daily by mouth. This dose was selected based on a phase I trial conducted by the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG). Treatment was continued until unacceptable toxicity or disease progression. RESULTS: Twenty-eight patients were enrolled at three NCIC CTG centers. Twenty-three patients had received prior chemotherapy; 12 patients had received three or more regimens. No objective responses were observed in 24 evaluable patients, although 8 patients had stable disease (median duration of 2.2 months). The most frequent drug related adverse events were diarrhea, rash and nausea. Eleven patients required dosing modification (hold or reduction), while 3 patients discontinued therapy because of toxicity. There were no treatment related deaths. CONCLUSIONS: ZD1839, when given at 750 mg/day to patients with pre-treated metastatic colorectal cancer, does not result in significant tumor regression.